Stabilized formulations containing anti-interleukin-6 receptor (IL-6R) antibodies

Patent metadata

Field	Value
Publication number	US-10072086-B2
Application number	US-201514861565-A
Country	US
Kind code	B2
Filing date	Sep 22, 2015
Priority date	Jan 8, 2010
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

The present invention provides pharmaceutical formulations comprising a human antibody that specifically binds to human interleukin-6 receptor (hIL-6R). The formulations may contain, in addition to an anti-hIL-6R antibody, at least one amino acid, at least one sugar, and/or at least one non-ionic surfactant. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability after storage for several months.

First claim

What is claimed is:

1. A stable pharmaceutical formulation comprising:
(i) a human antibody that specifically binds to human interleukin-6 receptor (hIL-6R), wherein the antibody is at a concentration of from about 25 mg/ml to about 200 mg/ml and comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:18 and a light chain variable region having the amino acid sequence of SEQ ID NO:26;
(ii) histidine at a concentration of from about 10 mM to about 25 mM;
(iii) arginine at a concentration of from about 25 mM to about 50 mM;
(iv) sucrose in an amount of from about 5% to about 10% w/v; and
(v) polysorbate in an amount of from about 0.1% to about 0.2% w/v, wherein the formulation has a pH of about 5.8, about 6.0, or about 6.2, and at least 90% of the native form of the antibody is recovered after 1 month of storage at 45° C., as determined by size exclusion chromatography.

2. The pharmaceutical formulation of claim 1 , wherein the histidine is at a concentration of 21 mM.

3. The pharmaceutical formulation of claim 2 , wherein the arginine is present at a concentration of 45 mM.

4. The pharmaceutical formulation of claim 3 , wherein the sucrose is present in an amount of 5% w/v.

5. The pharmaceutical formulation of claim 4 , wherein the polysorbate is present at a concentration of 0.2% w/v.

6. The pharmaceutical formulation of claim 5 that has a pH of 6.

7. The pharmaceutical formulation of claim 1 , comprising from 50 mg/mL to 180 mg/mL of the human antibody that specifically binds to hIL-6R.

8. The pharmaceutical formulation of claim 7 , comprising 150 mg/mL of said human antibody that specifically binds to hIL-6R.

9. The pharmaceutical formulation of claim 7 , comprising 175 mg/mL of said human antibody that specifically binds to hIL-6R.

10. The pharmaceutical formulation of claim 9 , wherein at least 90% of the native form of said antibody is recovered after nine months of storage at 5° C., as determined by size exclusion-high performance liquid chromatography (SE-HPLC).

11. The pharmaceutical formulation of claim 10 , wherein at least 95% of the native form of said antibody is recovered after nine months of storage at 5° C., as determined by size exclusion-high performance liquid chromatography (SE-HPLC).

12. The pharmaceutical formulation of claim 11 , wherein at least 96% of the native form of said antibody is recovered after nine months of storage at 5° C., as determined by size exclusion-high performance liquid chromatography (SE-HPLC).

13. The pharmaceutical formulation of claim 9 , wherein the formulation exhibits a viscosity of less than about 15 cPoise.

14. The pharmaceutical formulation of claim 9 , wherein the formulation exhibits a viscosity of less than about 12 cPoise.

15. The pharmaceutical formulation of claim 9 , wherein the formulation exhibits a viscosity of less than about 9 cPoise.

16. The pharmaceutical formulation of claim 1 , wherein the formulation is contained in a glass vial.

17. The pharmaceutical formulation of claim 1 , wherein the formulation is contained in a syringe.

18. The pharmaceutical formulation of claim 1 , wherein the formulation is contained in a microinfusor.

19. The pharmaceutical formulation of claim 17 , wherein said syringe comprises a fluorocarbon-coated plunger.

20. The pharmaceutical formulation of claim 17 , wherein said syringe is a low tungsten syringe.

21. A stable pharmaceutical formulation comprising:
(i) 25 to 200 mg/mL of a human antibody that specifically binds to human interleukin-6 receptor (hIL-6R), wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:18 and a light chain variable region having the amino acid sequence of SEQ ID NO:26;
(ii) about 21, 22, 23, 24 or 25 mM histidine;
(iii) about 3%, 4% or 5% w/v sucrose;
(iv) about 0.18%, 0.19% or 0.2% w/v polysorbate 20; and
(v) about 45 or 50 mM arginine,
wherein the formulation has a pH of about 6, and at least 90% of the native form of the antibody is recovered after 1 month of storage at 45° C., as determined by size exclusion chromatography.

22. A stable pharmaceutical formulation comprising:
(i) about 150 mg/mL of a human antibody that specifically binds to human interleukin-6 receptor (hIL-6R), wherein said antibody comprises a heavy chain and light chain variable region (HCVR/LCVR) amino acid sequence pair of SEQ ID NOs:18/26;
(ii) about 21 mM histidine;
(iii) about 5% sucrose;
(iv) about 0.2% polysorbate 20; and
(v) about 45 mM arginine,
wherein the formulation has a pH of about 6, and at least 90% of the native form of the antibody is recovered after 1 month of storage at 45° C., as determined by size exclusion chromatography.

23. A stable pharmaceutical formulation comprising:
(i) about 175 mg/mL of a human antibody that specifically binds to human interleukin-6 receptor (hIL-6R), wherein said antibody comprises a heavy chain and light chain variable region (HCVR/LCVR) amino acid sequence pair of SEQ ID NOs:18/26;
(ii) about 21 mM histidine;
(iii) about 5% sucrose;
(iv) about 0.2% polysorbate 20; and
(v) about 45 mM arginine,
wherein the formulation has a pH of about 6, and at least 90% of the native form of the antibody is recovered after 1 month of storage at 45° C., as determined by size exclusion chromatography.

24. The pharmaceutical formulation of claim 23 , wherein the formulation is contained in a stacked needle prefilled syringe.

25. The pharmaceutical formulation of claim 23 , wherein at least 96% of native form of said antibody is recovered after two months of storage at 5° C., as determined by size exclusion-high performance liquid chromatography.

26. The pharmaceutical composition of claim 1 , wherein the polysorbate is polysorbate 20.

Assignees

• Regeneron Pharma

Inventors

• Dix Daniel B
• Graham Kenneth S
• Kamen Douglas
• Walsh Scott M

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title